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Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent anion channel mostly expressed in epithelia. Accumulating evidence suggests that CF airway epithelia are overwhelmed by excessive inflammatory cytokines and prostaglandins (PGs), which eventually lead to the over-inflammatory condition observed in CF lung disease. However, the exact underlying mechanism remains elusive. In this study, we observed increased cyclooxygenase-2 (COX-2) expression and over-production of prostaglandin E2 (PGE2) in human CF bronchial epithelia cell line (CFBE41o−) with elevated NF-κB activity compared to a wild-type airway epithelial cell line (16HBE14o−). Moreover, we demonstrated that CFTR knockout mice had inherently higher levels of COX-2 and NF-κB activity, supporting the notion that lack of CFTR results in hyper-inflammatory signaling. In addition, we identified a positive feedback loop for production of PGE2 involving PKA and transcription factor, CREB. More importantly, overexpression of wild-type CFTR significantly suppressed COX-2 expression in CFBE41o− cells, and wild-type CFTR protein expression was significantly increased when 16HBE14o− cells were challenged with LPS as well as PGE2, indicating possible involvement of CFTR in negative regulation of COX-2/PGE2. In conclusion, CFTR is a negative regulator of PGE2-mediated inflammatory response, defect of which may result in excessive activation of NF-κB, leading to over production of PGE2 as seen in inflammatory CF tissues. J. Cell. Physiol. 227: 2759-2766, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]